Abstract
To provide evidence for the better clinical use of traditional Chinese medicine preparations (TCMPs), comparison of the pharmacological mechanisms between TCMPs with similar therapeutic effect is necessary. However, methodology for dealing with this issue is still scarce. Danhong injection (DHI) and Naoxintong capsule (NXT) are representative TCMPs for ischemic stroke (IS) treatment, which are also frequently used in combination. Here they were employed as research objects to demonstrate the feasibility of systems pharmacology approach in elucidation of the independent and combined effect of TCMPs. By incorporating chemical screening, target prediction, and network construction, a feasible systems pharmacology model has been established to systematically uncover the underlying action mechanisms of DHI, NXT, or their pair in IS treatment. Systematic analysis of the created TCMP-Compound-Target-Disease network revealed that DHI and NXT shared common targets such as PTGS2, F2, ADRB1, IL6, ALDH2, and CCL2, which were involved in the vasomotor system regulation, blood-brain barrier disruption, redox imbalance, neurotrophin activity, and brain inflammation. In comparative mechanism study, the merged DHI/NXT-IS PPI network and pathway enrichment analysis indicated that DHI and NXT exerted the therapeutic effects mainly through immune system and VEGF signaling pathways. Meanwhile, they had their own unique pathways, e.g., calcium signaling pathway for DHI and gap junction for NXT. While for their synergistic mechanism, DHI and NXT participated in chemokine signaling pathway, T cell receptor signaling pathway, VEGF signaling pathway, gap junction, and so on. Our study provided an optimized strategy for dissecting the different and combined effect of TCMPs with similar actions.
Highlights
Ischemic stroke (IS) is a common disease caused by intracranial or neck blood vessel occlusion that impairs blood flow to a portion of the brain and leads to subsequent cerebral necrosis [1]
A network pharmacology approach based on chemical, pharmacokinetic, and pharmacological data was employed to systematically investigate the comparative and synergistic effects of Danhong injection (DHI) and Naoxintong capsule (NXT) against IS
The overall procedure involved five steps (Figure 1): (1) the chemical ingredients of DHI and NXT were collected and evaluated by in silico ADME system to screen candidate compounds; (2) the putative targets of the candidate compounds and IS were data-mined from various databases and literatures; (3) a basal traditional Chinese medicine preparations (TCMPs)-Compound-Target-Disease network was constructed to illustrate the interaction among DHI/NXT, ingredients, targets and IS; (4) for comparative study of the action mechanisms, two protein-protein interaction (PPI) networks named DHI-IS and NXT-IS PPI network were merged and pathway enrichment analysis was separately performed to explore the common and unique mechanisms of DHI and NXT; (5) for the study of their synergistic effect, DHI-NXT-IS PPI network was established among DHIingredient targets, NXT-ingredient targets, and IS targets
Summary
Ischemic stroke (IS) is a common disease caused by intracranial or neck blood vessel occlusion that impairs blood flow to a portion of the brain and leads to subsequent cerebral necrosis [1]. Systems pharmacology method is widely perceived as an integral and efficient tool to study the complex molecular mechanisms of herbal medicines [24,25,26,27,28,29,30] This approach usually includes three steps, including active compounds screening, drug targets prediction, and network/pathway analysis [31, 32]. To provide evidence for the better clinical use of DHI and NXT, here we proposed a feasible systems pharmacologybased method to explore the similarities and differences of the pharmacological mechanisms between DHI and NXT Their synergistic mechanism in treatment of IS was investigated. No work has been reported about the mechanism comparison and synergistic effect of DHI and NXT
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